This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Melani, C. Articles by Colombo, M. P. Search for Related Content PubMed PubMed Citation Articles by Melani, C. Articles by Colombo, M. P.

Amino-Biphosphonate–Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma

¹ Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Fondazione Istituto Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy and ² Department of Anatomy and the Biomedical Sciences Program, University of California, San Francisco, California

Requests for reprints: Cecilia Melani, Immunotherapy and Gene Therapy Unit, Fondazione Istituto Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, via G. Venezian, 1, 20133 Milan, Italy. Phone: 39-0223902212; Fax: 39-0223902630; E-mail: cecilia.melani{at}istitutotumori.mi.it.

BALB-neuT mice expressing an activated rat c-erbB-2/neu transgene under the mouse mammary tumor virus long terminal repeat show enhanced hematopoiesis with hyperproduction of myeloid-derived suppressor cells (MDSC) because of vascular endothelial growth factor (VEGF) secreted by the tumor. Here, we show that both tumor and stromal cells express matrix metalloproteinase-9 (MMP-9), thereby increasing the levels of pro–MMP-9 in the sera of tumor-bearing mice. Treatment with amino-biphosphonates impaired tumor growth, significantly decreased MMP-9 expression and the number of macrophages in tumor stroma, and reduced MDSC expansion both in bone marrow and peripheral blood by dropping serum pro–MMP-9 and VEGF. We dissected the role of tumor-derived MMP-9 from that secreted by stromal leukocytes by transplanting bone marrow from MMP-9 knockout mice into BALB-neuT mice. Although bone marrow progenitor–derived MMP-9 had a major role in driving MDSC expansion, amino-biphosphonate treatment of bone marrow chimeras further reduced both myelopoiesis and the supportive tumor stroma, thus enhancing tumor necrosis. Moreover, by reducing MDSC, amino-biphosphonates overcome the tumor-induced immune suppression and improved the generation and maintenance of antitumor immune response induced by immunization against the p185/HER-2. Our data reveal that suppression of MMP-9 activity breaks the vicious loop linking tumor growth and myeloid cell expansion, thus reducing immunosuppression. Amino-biphosphonates disclose a specific MMP-9 inhibitory activity that may broaden their application above their current usage. [Cancer Res 2007;67(23):11438–46]

This article has been cited by other articles:

				T. Van den Wyngaert, M. T. Huizing, and J. B. Vermorken Disambiguating the bisphosphonates Ann. Onc., July 1, 2008; 19(7): 1357 - 1359. [Full Text] [PDF]